A large body of information has accumulated about the molecular biology of MMTV (reviewed in Slagle, B. L. et al., 1987, in "Cellular and Molecular Biology of Mammary Cancer", Kidwell et al., eds., Plenum Press, NY. pp 275-306). Mouse mammary tumor virus (MMTV) is associated with a high incidence of breast cancer in certain strains of mice (over 90% among females), and has been regarded as a potential model for human disease.
The MMTV virus does not carry a transforming oncogene, but rather acts as an insertional mutagen with several proviral insertion loci designated int-1 or wnt-1 (Nusse R. et al., 1982, Cell 31:99-109) int-2 (Peters, G. et al., 1983, Cell 33:369-377) int-3 (Gallahan, D. et al., 1987, J. Virol. 61:218-220) int-4 (Roelink, H. et al., 1990, Proc. Natl. acad. Sci. USA 87:4519-4523) and int-5 (Morris, V. L., et al. 1991, Oncogene Research 6:53-63), which encode for growth factors or other related proteins. These genes are not expressed in normal mammary tissue but become activated after integration of MMTV provirus into the adjacent chromosomal DNA.
The human homolog of the int-2 locus has been located on chromosome 11 (Casey, G. et al., 1986, Mol. Cell Biol. 6:502-510) and has been found amplified (in 15% of the breast cancers) and also expressed (Lidereau, R. et al., 1988, Oncogene Res 2:285-291; Zhou, D. J. et al., 1988, Oncogene 2:279-282; Liscia, D. S. et al., 1989, Oncogene 4:1219-1224; Meyers, S. L. et al., 1990, Cancer Res 50:5911-5918). It may be significant that in tumors from Parsi women, who have a high incidence of breast tumors, the int-2 locus is amplified in 50% of the cases (Barnabas-Sohi, N. et al., 1993, Breast Dis. 6:13-26). The amplification of int-2 and other genes in 11q13 is indicative of poor prognosis (Schuwring, E. et al., 1992, Cancer Research 52:5229-5234; Champeme, M-H, et al., 1995, Genes, Chromosomes and Cancer 12:128-133). Both mouse and human int-2 have been sequenced (Moore, R. et al., 1986, EMBO J 5:919-924). The gene encodes a protein of about 27 kilodaltons (KD) which shows homology to both basic and acidic fibroblast growth factors (Dickson, C. et al. 1987, Nature (London) 326:833).
However, efforts to demonstrate the presence of viruses in human breast cancer through search for viral particles, immunological cross-reactivity, or sequence homology have yielded contradictory results. Detectable MMTV env gene-related antigenic reactivity has been found in tissue sections of breast cancer (Mesa-Tejada et al., 1978, Proc. Natl. Acad. Sci. USA 75:1529-1533; Levine, P. et al., 1980, Proc. Am. Assoc. Cancer Res. 21:170; Lloyd, R. et al., 1983, Cancer 51:654-661), breast cancer cells in culture (Litvinov, S. V. and Golovkina, T. V., 1989, Acta Virologica 33:137-142), human milk (Zotter S. et al., 1980, Eur. J. Cancer 16:455-467) in sera of patients (Day, N. K. et al., 1981, Proc. Natl. Acad. Sci. USA 78:2483-2487), in cyst fluid (Witkin, S. S. et al., 1981, J. Clin. Invest. 67:216-222) and in particles produced by a human breast carcinoma cell line (Keydar, I. et al., 1984, Proc. Natl. Acad. Sci. USA 81:4188-4192). Sequence homology to MMTV has been found in human DNA under low stringency conditions of hybridization (Callahan, R. et al., 1982, Proc. Natl. Acad. Sci. USA 79:5503-5507) and RNA related to MMTV has been detected in human breast cancer cells (Axel, R. et al., 1972, Nature 235:32-36). The presence of MMTV related sequences in lymphocytes from patients with breast cancer has been reported (Crepin, M. et al., 1984, Biochem. Biophys. Res. Comm. 118:324-331), as well as detection of reverse transcriptase (RT) activity in their monocytes (Al-Sumidaie, A. M. et al., 1988, Lancet 1:5-8). May and Westley (May and Westley, 1989, Cancer Research 49:3879-3883) have reported the presence of MMTV-like sequences arranged as tandem repeats only in DNA from breast cancer cells.
These results have been difficult to interpret, and theories linking MMTV or a related virus with human breast cancer have fallen out of favor, in view of the relatively recent discovery of human endogenous retroviral sequences ("HERs"; Westley, B. et al., 1986, J. Virol. 60:743-749; Ono, M. et al., 1986, J. Virol. 60:589-598; Faff, 0. et al., 1992, J. Gen. Virology 73:1087-1097). Data which could be interpreted to demonstrate the presence of MMTV-related sequences could be more readily explained by endogenous human retroviral sequences. Adding further confusion to the picture, env-gene related antigenicity has been detected in epitopes of human proteins (Hareuveni, M. et al., 1990, Int. J. Cancer 46:1134-1135).